Outcomes for people with TB by disease severity at presentation.

There is substantial heterogeneity in disease presentation for individuals with TB disease, which may correlate with disease outcomes. We estimated disease outcomes by disease severity at presentation among individuals with TB during the pre-chemotherapy era.We extracted data on people with TB enrolled between 1917 and 1948 in the USA, stratified by three disease severity categories at presentation using the U.S. National Tuberculosis Association diagnostic criteria. These criteria were based largely on radiographic findings ("minimal", "moderately advanced", and "far advanced"). We used Bayesian parametric survival analysis to model the survival distribution overall, and by disease severity and Bayesian logistic regression to estimate the severity-level specific natural recovery odds within 3 years.People with minimal TB at presentation had a 2% (95% CrI 0-11%) probability of TB death within 5 years vs. 40% (95% CrI 15-68) for those with far advanced disease. Individuals with minimal disease had 13.62 times the odds (95% CrI 9.87-19.10) of natural recovery within 3 years vs. those with far advanced disease.Mortality and natural recovery vary by disease severity at presentation. This supports continued work to evaluate individualized (e.g., shortened or longer) regimens based on disease severity at presentation, identified using radiography..

Survival of people with untreated TB: effects of time, geography and setting.

BACKGROUND: An estimated 40% of people who developed TB in 2021 were not diagnosed or treated. Pre-chemotherapy era data are a rich resource on survival of people with untreated TB. We aimed to identify heterogeneities in these data to inform their more precise use.METHODS: We extracted survival data from pre-chemotherapy era papers reporting TB-specific mortality and/or natural recovery data. We used Bayesian parametric survival analysis to model the survival distribution, stratifying by geography (North America vs. Europe), time (pre-1930 vs. post-1930), and setting (sanitoria vs. non-sanitoria).RESULTS: We found 12 studies with TB-specific mortality data. Ten-year survival was 69% in North America (95% CI 54-81) and 36% in Europe (95% CI 10-71). Only 38% (95% CI 18-63) of non-sanitorium individuals survived to 10 years compared to 69% (95% CI 41-87) of sanitoria/hospitalized patients. There were no significant differences between people diagnosed pre-1930 and post-1930 (5-year survival pre-1930: 65%, 95% CI 44-88 vs. post-1930: 72%, 95% CI 41-94).CONCLUSIONS: Mortality and natural recovery risks vary substantially by location and setting. These heterogeneities need to be considered when using pre-chemotherapy data to make inferences about expected survival of people with undiagnosed TB.

Quantifying TB transmission: a systematic review of reproduction number and serial interval estimates for tuberculosis.

Tuberculosis (TB) is the leading global infectious cause of death. Understanding TB transmission is critical to creating policies and monitoring the disease with the end goal of TB elimination. To our knowledge, there has been no systematic review of key transmission parameters for TB. We carried out a systematic review of the published literature to identify studies estimating either of the two key TB transmission parameters: the serial interval (SI) and the reproductive number. We identified five publications that estimated the SI and 56 publications that estimated the reproductive number. The SI estimates from four studies were: 0.57, 1.42, 1.44 and 1.65 years; the fifth paper presented age-specific estimates ranging from 20 to 30 years (for infants <1 year old) to <5 years (for adults). The reproductive number estimates ranged from 0.24 in the Netherlands (during 1933-2007) to 4.3 in China in 2012. We found a limited number of publications and many high TB burden settings were not represented. Certain features of TB dynamics, such as slow transmission, complicated parameter estimation, require novel methods. Additional efforts to estimate these parameters for TB are needed so that we can monitor and evaluate interventions designed to achieve TB elimination.

The burden of multidrug-resistant tuberculosis in children.

BACKGROUND: Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB). METHODS: We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients. RESULTS: Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified. DISCUSSION: The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.

Estimating the global burden of multidrug-resistant tuberculosis among prevalent cases of tuberculosis.

BACKGROUND: Estimates of the multidrug-resistant tuberculosis (MDR-TB) burden are based on incomplete, infrequently updated data among a limited pool of notified or incident pulmonary TB cases. METHODS: Using World Health Organization data reported by 217 countries/territories in 2014, we calculated the MDR-TB burden among prevalent TB cases and compared these with estimates among incident and notified TB patients. We also compared treatment coverage across estimates. RESULTS: Among prevalent TB patients worldwide in 2014, we estimate that 555 545 (95% credible bounds 499 340-617 391) MDR-TB cases occurred. This is 85% more than the 300 000 estimated among notified cases, and 16% more than the 480 000 among incident cases. Only 20% of MDR-TB cases among prevalent-compared to 37% of MDR-TB among notified-TB patients had access to MDR-TB treatment. Applying prior estimates, only 10% of MDR-TB cases will have successful outcomes. CONCLUSION: Estimates based on likely-to-be-diagnosed cases of MDR-TB overlook a significant proportion of morbidity, mortality, and transmission that occur in undiagnosed, untreated, prevalent TB patients. Even though it may still likely underestimate the true disease burden, MDR-TB among patients with prevalent TB represents a closer approximation of disease burden than currently reported indicators. Progress toward elimination or control depends on policies guided by a more complete representation of the disease burden.

Isoniazid-resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.

Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities.

On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.

Two methods for setting child-focused tuberculosis care targets.

OBJECTIVE: To allocate resources for household contact investigations, tuberculosis (TB) programs need estimates of the numbers of child contacts requiring care. DESIGN: We developed two methods to estimate annual numbers of child contacts aged 0-14 years requiring evaluation and treatment. Method 1 combines local data using simple formulas. Using publicly available data, Method 2 uses a linear regression model based on Demographic and Health Survey and World Bank data to estimate the number of children per household, then combines these results with case notifications and risk estimates of disease and infection. RESULTS: Applying Method 1 to data from Malawi indicated that every year ~21 000 child contacts require evaluation and ~1900 should be diagnosed with TB. Applying Method 2 to all countries suggested that, globally, 2.41 million (95% uncertainty interval [UI] 2.36-2.46) children aged <5 years, and 5.07 million (95%UI 4.81-5.34) children aged 5-14 years live in households of adult patients with known TB. Of these, 239 014 (95%UI 118 649-478581) and 419 816 (95%UI 140600-1 268805), respectively, will have TB. An additional 848 453 (95%UI 705838-1 017551) and 2660 885 (95%UI 2080517-3 413 189), respectively, will be infected. CONCLUSION: It is feasible to use available data to set programmatic evaluation and treatment targets to improve care for child contacts of patients with TB.

Objectif : Pour allouer des ressources aux recherches de contacts domiciliaires, les programmes de lutte contre la tuberculose (TB) ont besoin d'estimations du nombre d'enfants contacts nécessitant une prise en charge.Schéma : Nous avons élaboré deux méthodes afin d'estimer les nombres annuels d'enfants contacts âgés de 0­14 ans requérant une évaluation et un traitement. La Méthode 1 combine des données locales utilisant des formules simples. En utilisant les données disponibles publiquement, la Méthode 2 se sert d'un modèle de régression linéaire basé sur les données de l'Enquête Démographie et Santé et celles de la Banque Mondiale afin d'estimer le nombre d'enfants dans chaque famille, puis de combiner ces résultats avec ceux de la déclaration des cas et des estimations de risque de maladie et d'infection.Résultats : En appliquant la Méthode 1 aux données du Malawi, nous avons abouti à ce que ~21 000 enfants contacts par an requéraient une évaluation et ~1900 devraient avoir un diagnostic de TB. Appliquer la Méthode 2 à tous les pays a suggéré que, dans le monde, 2,41 millions d'enfants âgés de <5 ans (intervalle d'incertitude [II] à 95% 2,36­2,46 millions) et 5,07 millions (II95% 4,81­5,34 millions) d'enfants âgés de 5­14 ans vivent dans des foyers comprenant un patient adulte atteint de TB chaque année. Parmi eux, 239 014 (II95% 118 649­478 581) et 419 816 (II95% 140 600­1 268 805), respectivement, auront la TB et 848 453 autres enfants (II95% 705838­1017 551) et 2660 885 (II95% 2080 517­3413 189) seront infectés.Conclusion : Il est possible d'utiliser les données disponibles pour établir des objectifs d'évaluation programmatique et de traitement afin d'améliorer la prise en charge des enfants contacts de patients tuberculeux.

Objetivo: Para designar los recursos necesarios para la evaluación de contactos de pacientes con tuberculosis (TB), los programas necesitan estimados de cuántos contactos niños requieren atención.Diseño: Desarrollamos dos métodos de estimar cuántos contactos que tienen 0­14 años requieren evaluación y tratamiento cada año. Método 1 usa información local y fórmulas sencillos. Usando información pública, Método 2 usa un modelo de regresión lineal basado en datos de las Encuestas Demográficas y de Salud y del Banco Mundial para estimar el número de niños en cada domicilio, y luego combina estos resultados con números reportados de casos de TB y con estimados del riesgo de enfermedad e infección con TB.Resultados: Aplicando el Método 1 a datos de Malawi indica que cada año, ~21 000 contactos niños deben ser evaluados y ~1900 deben ser diagnosticados con TB. Aplicando el Método 2 a datos de todos los países del mundo indica que cada año, al nivel mundial, hay 2,41 millón (intervalo de incertidumbre [II] de 95% 2,36­2,46 millón) de niños de edad <5 años, y 5,07 millón (II95% 4,81­5,34 millón) de niños que tienen 5­14 años, quienes viven en domicilios de adultos que se sabe son pacientes con TB. De estos niños, 239 014 (II95% 118649­478 581) y 419816 (II95% 140600­1 268 805), respectivamente, estarán enfermos con TB. Además, 848 453 (II95% 705838­1 017551) y 2 660 885 (II95% 2080 517­3 413189) estarán infectados con TB pero no enfermos.Conclusión: Es factible usar datos disponibles para generar metas programáticas para la evaluación y el tratamiento, con el fin de mejorar la atención a los contactos niños de pacientes con TB.

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete.

Geographical heterogeneity of multidrug-resistant tuberculosis in Georgia, January 2009 to June 2011.

In 2011, Georgia, in the Caucasus, reported that 11% of new and 32% of previously treated tuberculosis (TB) cases nationally had multidrug-resistant TB (MDR-TB). To help understand the mechanisms driving these high risks of drug-resistance and plan for targeted interventions, we identified geographical variability in the MDR-TB burden in Georgia and patient-level MDR-TB risk factors. We used routinely collected surveillance data on notified TB cases to estimate the MDR-TB incidence/100,000 people and the percentage of TB cases with MDR-TB for each of 65 districts and regression modelling to identify patient-level MDR-TB risk factors. 1,795 MDR-TB cases were reported (January 2009­June 2011); the nationwide notified MDR-TB incidence was 16.2/100,000 but far higher (837/100,000) in the penitentiary system. We found substantial geographical heterogeneity between districts in the average annual MDR-TB incidence/100,000 (range: 0.0­5.0 among new and 0.0­18.9 among previously treated TB cases) and the percentage of TB cases with MDR-TB (range: 0.0%­33.3% among new and 0.0%­75.0% among previously treated TB cases). Among treatment-naïve individuals, those in cities had greater MDR-TB risk than those in rural areas (increased odds: 43%; 95% confidence interval: 20%­72%). These results suggest that interventions for interrupting MDR-TB transmission are urgently needed in prisons and urban areas.

Outcomes of children treated for tuberculosis with second-line medications in Georgia, 2009-2011.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a major public threat in countries of the former Soviet Union, including Georgia. There are few studies of pediatric DR-TB cases, especially at a national level. OBJECTIVE: To report the characteristics and treatment outcomes of pediatric multidrug-resistant TB (MDR-TB) cases in Georgia. METHODS: We extracted data on all pediatric (age <16 years) MDR-TB cases notified in Georgia from 2009 to 2011. We assessed the baseline and treatment characteristics and treatment outcomes of this cohort. RESULTS: Between 2009 and 2011, there were 45 notified pediatric DR-TB cases in Georgia. Just over half had previously received anti-tuberculosis treatment and the median age was 7.7 years. Time from diagnosis to treatment was short (median 16 days), and the median length of treatment was 20.2 months. Of those not still on treatment, 77.1% (95%CI 61.0-87.9) had a successful outcome. CONCLUSIONS: One of the first reports of pediatric DR-TB treatment outcomes at a national level, this study demonstrates that successful outcomes can be achieved.

Risk factors and timing of default from treatment for non-multidrug-resistant tuberculosis in Moldova.

SETTING: The Republic of Moldova, in Eastern Europe, has among the highest reported nationwide proportions of tuberculosis (TB) patients with multidrug-resistant tuberculosis (MDR-TB) worldwide. Default has been associated with increased mortality and amplification of drug resistance, and may contribute to the high MDR-TB rates in Moldova. OBJECTIVE: To assess risk factors and timing of default from treatment for non-MDR-TB from 2007 to 2010. DESIGN: A retrospective analysis of routine surveillance data on all non-MDR-TB patients reported. RESULTS: A total of 14.7% of non-MDR-TB patients defaulted from treatment during the study period. Independent risk factors for default included sociodemographic factors, such as homelessness, living alone, less formal education and spending substantial time outside Moldova in the year prior to diagnosis; and health-related factors such as human immunodeficiency virus co-infection, greater lung pathology and increasing TB drug resistance. Anti-tuberculosis treatment is usually initiated within an institutional setting in Moldova, and the default risk was highest in the month following the phase of hospitalized treatment (among civilians) and after leaving prison (among those diagnosed while incarcerated). CONCLUSIONS: Targeted interventions to increase treatment adherence for patients at highest risk of default, and improving the continuity of care for patients transitioning from institutional to community care may substantially reduce risk of default.

The prevalence, distribution and severity of detectable pathological lesions in badgers naturally infected with Mycobacterium bovis.

The Randomized Badger Culling Trial (RBCT) began in 1998 to determine the impact of badger culling in controlling bovine tuberculosis in cattle. A total of 1166 badgers (14% of total) proactively culled during the RBCT were found to be tuberculous, offering a unique opportunity to study the pathology caused by Mycobacterium bovis in a large sample of badgers. Of these, 39% of adults (approximately 6% of all adults culled) had visible lesions (detectable at necropsy) of bovine tuberculosis; cubs had a lower prevalence of infection (9%) but a higher percentage of tuberculous cubs (55.5%) had visible lesions. Only approximately 1% of adult badgers had extensive, severe pathology. Tuberculous badgers with recorded bite wounds (approximately 5%) had a higher prevalence of visible lesions and a different distribution of lesions, suggesting transmission via bite wounds. However, the predominance of lesions in the respiratory tract indicates that most transmission occurs by the respiratory route.

Incorporation of the nuclear pore basket protein nup153 into nuclear pore structures is dependent upon lamina assembly: evidence from cell-free extracts of Xenopus eggs.

In cell-free extracts of Xenopus eggs that support the assembly of replication-competent nuclei, we found that lamin B(3) specifically associates with four polypeptides (termed SLAPs, soluble lamin associated proteins). Here, one SLAP is identified as the nuclear pore complex protein Nup153, one member of the F/GXFG motif-containing nucleoporins. In vitro translated Nup153 and lamin B(3) co-immunoprecipitate, and lamin B(3) interacts specifically with the C-terminal domain of Nup153. During nuclear envelope assembly, other F/GXFG-containing nucleoporins are incorporated into the nuclear envelope preceding lamina assembly. Incorporation of Nup153 occurs at the same time as lamina assembly. When lamina assembly is prevented using the dominant-negative mutant XlaminB delta 2+, Nup153 does not appear at the nuclear envelope, while other F/GXFG-containing nucleoporins and Nup93 are recruited normally. When the lamina of pre-assembled nuclei is disrupted using the same dominant-negative mutant, the distribution of other nucleoporins is unaffected. However, Nup153 recruitment at the nuclear envelope is lost. Our results indicate that both the recruitment and maintenance of Nup153 at the pore are dependent upon the integrity of the lamina.